Therapeutic compounds

ABSTRACT

Disclosed herein are compounds of the formula 
     
       
         
         
             
             
         
       
     
     therapeutic methods, compositions, and medicaments related thereto are also disclosed.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 60/806,813, filed Jul. 10, 2006, which is hereby incorporated byreference in its entirety.

DESCRIPTION OF THE INVENTION

Disclosed herein are compounds of the formula

wherein a dashed line represents the presence or absence of a bond;

Y is an organic acid functional group, or an amide or ester thereofcomprising up to 14 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced by S or O;or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced by S or O; U¹ is independently hydrogen; OH; O; S;F; Cl; Br; I; CN; or O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; J¹and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃; Z is S, SO, SO₂, NR, NCOR, or NSO₂R, wherein R isH or C₁₋₆ hydrocarbyl, and B is aryl or heteroaryl.

Also disclosed herein is a carboxylic acid or a bioisostere thereof,said carboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O; U¹ isindependently hydrogen; OH; O; S; F; Cl; Br; I; CN; or O-alkyl having 1,2, 3, 4, 5 or 6 carbon atoms; J¹ and J² are independently hydrogen; F;Cl, Br; I; O; OH; CN; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms; or CF₃; Z is S, SO, SO₂,NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl, and B is aryl orheteroaryl.

Any structure depicted herein, whether alone or presented with otherstructures, is contemplated as an individual embodiment.

Furthermore, for each individual structure presented herein, anembodiment is contemplated which comprises the compound of thestructure, and/or one or more prodrugs of compounds of the structure,and/or one or more pharmaceutically acceptable salts of the compounds ofthe structure.

An embodiment is also contemplated which comprises the compound of thestructure, and/or one or more pharmaceutically acceptable salts of thecompounds of the structure.

An embodiment is also contemplated which comprises the compound of thestructure, and/or one or more prodrugs of compounds of the structure.

Since a dashed line represents the presence or absence of a bond,compounds such as those according to the structures below are possible.

“Bioisosteres are substituents or groups that have chemical or physicalsimilarities, and which produce broadly similar biological properties.”Silverman, Richard B., The Organic Chemistry of Drug Design and DrugAction, 2^(nd) Edition, Amsterdam: Elsevier Academic Press, 2004, p. 29.

While not intending to be limiting, organic acid functional groups arebioisoteres of carboxylic acids. An organic acid functional group is anacidic functional group on an organic molecule. While not intending tobe limiting, organic acid functional groups may comprise an oxide ofcarbon, sulfur, or phosphorous. Thus, while not intending to limit thescope of the invention in any way, in certain compounds Y is acarboxylic acid, sulfonic acid, or phosphonic acid functional group.

Additionally, an amide or ester of one of the organic acids mentionedabove comprising up to 14 carbon atoms is also contemplated. In anester, a hydrocarbyl moiety replaces a hydrogen atom of an acid such asin a carboxylic acid ester, e.g. CO₂Me, CO₂Et, etc.

In an amide, an amine group replaces an OH of the acid. Examples ofamides include CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, and CONH(CH₂CH₂OH)where R² is independently H, C₁-C₆ alkyl, phenyl, or biphenyl. Moietiessuch as CONHSO₂R² are also amides of the carboxylic acid notwithstandingthe fact that they may also be considered to be amides of the sulfonicacid R²—SO₃H. The following amides are also specifically contemplated,CONSO₂-biphenyl, CONSO₂-phenyl, CONSO₂-heteroaryl, and CONSO₂-naphthyl.The biphenyl, phenyl, heteroaryl, or naphthyl may be substituted orunsubstituted.

Han et. al. (Biorganic & Medicinal Chemistry Letters 15 (2005)3487-3490) has recently shown that the groups shown below are suitablebioisosteres for a carboxylic acid. The activity of compounds with thesegroups in inhibiting HCV NS3 protease was comparable to or superior tosimilar compounds where the group is replaced by CO₂H. Thus, Y could beany group depicted below.

Carboxylic Acid Bioisosteres According to Han et. al.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising up to 14 carbonatoms. An ether is a functional group wherein a hydrogen of an hydroxylis replaced by carbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc. These groupsare also bioisosteres of a carboxylic acid.

“Up to 14 carbon atoms” means that the entire Y moiety, including thecarbonyl carbon of a carboxylic acid ester or amide, and both carbonatoms in the —CH₂O—C of an ether has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 carbon atoms.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group.

While not intending to be limiting, examples of compounds having theidentified Y are depicted below. In these examples R is H orhydrocarbyl, subject to the constraints defined herein. Each structurebelow represents a specific embodiment which is individuallycontemplated, as well as pharmaceutically acceptable salts and prodrugsof compounds which are represented by the structures. However, otherexamples are possible which may not fall within the scope of thestructures shown below.

Organic Acids Esters Amides M¹—CO₂H M¹—CO₂R M¹—CO₂NR₂ Carboxylic AcidCarboxylic Acid Ester Carboxylic Acid Amide M¹—P(O)(OH)₂ M¹—P(O)(OH)RM¹—P(O)(OH)NR₂ Phosponic Acid Phosphonic Acid Ester Phosphonic AcidAmide M¹—SO₃H M¹—SO₃R M¹—SO₃NR₂ Sulfonic Acid Sulfonic Acid EsterSulfonic Acid Amide M¹—CH₂OH M¹—CH₂OR Y is hydroxymethyl Ether

A tetrazolyl functional group is another bioisostere of a carboxylicacid. An unsubstituted tetrazolyl functional group has two tautomericforms, which can rapidly interconvert in aqueous or biological media,and are thus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₂ are considered to be within the scope of the term “tetrazolyl.”

In one embodiment, Y is an organic acid functional group, or an amide orester thereof comprising up to 14 carbon atoms; or Y is hydroxymethyl oran ether thereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group.

In another embodiment, Y is CO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂,CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

According to Silverman (p. 30), the moieties shown below are alsobioisosteres of a carboxylic acid.

Carboxylic Acid Bioisosteres According to Silverman

Orlek et al. (J. Med. Chem. 1991, 34, 2726-2735) described oxadiazolesas suitable bioisosteres for a carboxylic acid. These ester replacementswere shown to be potent muscarinic agonists having improved metabolicstability. Oxadiazoles were also described by Anderson et al. (Eur. J.Med. Chem. 1996, 31, 417-425) as carboxamide replacements havingimproved in vivo efficacy at the benzodiazepine receptor.

Carboxylic Acid Bioisosteres According to Orlek et. al.

Kohara et al. (J. Med. Chem. 1996, 39, 5228-5235) described acidicheterocycles as suitable bioisosteres for a tetrazole. These carboxylicacid replacements were shown to be potent angiotensin II receptorantagonists having improved metabolic stability.

Tetrazole Bioisosteres According to Kohara et al.

Drysdale et al. (J. Med. Chem. 1992, 35, 2573-2581) have describedcarboxylic acid mimics of non-peptide CCK-B receptor antagonists. Thebinding affinities of many of the bioisosteres are similar to the parentcarboxylic acid.

Carboxylic Acid Bioisosteres According to Drysdale et al.

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O.

While not intending to be limiting, A may be —(CH₂)₆—,cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S or O. For example, A maybe a moiety where S replaces one or two carbon atoms such as one of thefollowing or the like.

Alternatively, A may be a moiety where O replaces one or two carbonatoms such as one of the following or the like.

Alternatively, A may have an O replacing one carbon atom and an Sreplacing another carbon atom, such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3,or 4, and wherein one CH₂ may be replaced with S or O. In other words,while not intending to limit the scope of the invention in any way, inone embodiment A comprises 1, 2, 3, or 4 CH₂ moieties and Ar, e.g.—CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—, —(CH₂)₂—Ar—(CH₂)₂—,and the like;

in another embodiment A comprises: O; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,—O—CH₂—Ar—(CH₂)₂, and the like; orin another embodiment A comprises: S; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—,—S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺ salt. Any cation of thesalt is not counted in the “4 or less heavy atoms.” Thus, thesubstituent may be

hydrocarbyl having up to 4 carbon atoms, including alkyl up to C₄,alkenyl, alkynyl, and the like;hydrocarbyloxy up to C₃;organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and saltsthereof;

CF₃;

halo, such as F, Cl, or Br;hydroxyl;

NH₂ and alkylamine functional groups up to C₃;

other N or S containing substituents such as CN, NO₂, and the like;and the like.

In one embodiment A is —(CH₂)_(m)-Ph-(CH₂)_(o)— wherein the sum of m ando is 1, 2, or 3, and wherein one CH₂ may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂-Ph-OCH₂—. In another embodiment, Ph is attached at the 1 and 3positions, otherwise known as m-interphenylene, such as when A has thestructure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂O(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)3S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)3—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene,

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

Compounds according to the each of the structures depicted below arepossible.

U¹ is independently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

In one embodiment, U¹ is hydrogen.

In one embodiment, U¹ is OH.

In one embodiment, U¹ is O.

In one embodiment, U¹ is S.

In one embodiment, U¹ is F.

In one embodiment, U¹ is Cl.

In one embodiment, U¹ is Br.

In one embodiment, U¹ is I.

In one embodiment, U¹ is CN.

In one embodiment, U¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃.

In one embodiment, J¹ is hydrogen.

In one embodiment, J¹ is F.

In one embodiment, J¹ is Cl.

In one embodiment, J¹ is Br.

In one embodiment, J¹ is I.

In one embodiment, J¹ is O.

In one embodiment, J¹ is OH.

In one embodiment, J¹ is CN.

In one embodiment, J¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, J¹ is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

In one embodiment, J¹ is CF₃.

In one embodiment, J² is hydrogen.

In one embodiment, J² is F.

In one embodiment, J² is Cl.

In one embodiment, J² is Br.

In one embodiment, J² is I.

In one embodiment, J² is O.

In one embodiment, J² is OH.

In one embodiment, J² is CN.

In one embodiment, J² is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, J² is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

In one embodiment, J² is CF₃.

Thus, compounds according to the structures shown below are possible.

Z is S, SO, SO₂, NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl.

Thus, compounds such as shown below are possible.

In one embodiment, Z is S.

In another embodiment, Z is NH.

In another embodiment, Z is SO.

In another embodiment, Z is SO₂.

In another embodiment, Z is NCH₃.

In another embodiment, Z is NC₂H₅.

In another embodiment, Z is NC₃H₇.

In another embodiment, Z is NC₄H₉.

In another embodiment, Z is NC₅H₁₁.

In another embodiment, Z is NC₆H₁₃.

In another embodiment, Z is N-phenyl.

In another embodiment, Z is NSO₂CH₃.

In another embodiment, Z is NCOCH₃.

B is aryl or heteroaryl.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O⁻Na⁺ salt or CO₂H may form a CO₂—K⁺ salt.Any cation of the salt is not counted in the 20 non-hydrogen atoms.Thus, while not intending to limit the scope of the invention in anyway, a substituent may be:

hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen suchas alkyl, alkenyl, alkynyl, and the like, including linear, branched orcyclic hydrocarbyl, and combinations thereof;hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,O-cyclohexyl, etc, up to 19 carbon atoms;other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the like;thioether substituents including S-hydrocarbyl and other thioethersubstituents;hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,etc, up to 19 carbon atoms;nitrogen substituents such as NO₂, CN, and the like, includingamino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like;carbonyl substituents, such as CO₂H, ester, amide, and the like;halogen, such as chloro, fluoro, bromo, and the likefluorocarbyl, such as CF₃, CF₂CF₃, etc.;phosphorous substituents, such as PO₃ ²⁻, and the like;sulfur substituents, including S-hydrocarbyl, SH, SO₃H, SO₂-hydrocarbyl,SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl and are also substitutedphenyl. For this type of polycyclic ring system, an aromatic orheteroaromatic ring, not a non-aromatic ring, must be attached to theremainder of the molecule, i.e. the part of the molecule that is not B.In other words, in any structure depicting —B herein, where — is a bond,the bond is a direct bond to an aromatic ring. Another embodiment is acompound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

Another embodiment is a compound according to the structure

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

Alkyl is hydrocarbyl having no double or triple bonds including:linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl,and the like;branched alkyl such as isopropyl, branched butyl isomers (i.e.sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl,etc), branched hexyl isomers, and higher branched alkyl fragments;cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.; andalkyl fragments consisting of both cyclic and noncyclic components,whether linear or branched, which may be attached to the remainder ofthe molecule at any available position including terminal, internal, orring carbon atoms.

Alkenyl is hydrocarbyl having one or more double bonds including

linear alkenyl, branched alkenyl, cyclic alkenyl, and combinationsthereof in analogy to alkyl.

Alkynyl is hydrocarbyl having one or more triple bonds including linearalkynyl, branched alkynyl, cyclic alkynyl and combinations thereof inanalogy to alkyl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like. Aryl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.Arylalkyl is alkyl which is substituted with aryl. In other words alkylconnects aryl to the remaining part of the molecule.Examples are —CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl mayor may not be hydrocarbyl, depending upon whether the aryl portion hassubstituents with heteroatoms.Unconjugated dienes or polyenes have one or more double bonds which arenot conjugated. They may be linear, branched, or cyclic, or acombination thereof.

Combinations of the above are also possible. C₁₋₃ alkyl is alkyl having1, 2, or 3 carbon atoms. C₁₋₃ alkoxy is —O-alkyl having 1, 2, or 3carbon atoms.

In another embodiment, B is substituted or unsubstituted phenyl.

In another embodiment, B is substituted or unsubstituted thienyl.

In another embodiment, B is substituted or unsubstituted naphthyl.

In another embodiment, B is substituted or unsubstituted furyl.

In another embodiment, B is substituted or unsubstituted pyridinyl.

In another embodiment, B is substituted or unsubstituted benzothienyl.

In another embodiment, B is substituted or unsubstituted indanyl.

In another embodiment, B is substituted or unsubstituted tetralonyl.

In another embodiment, B has 1, 2, 3, 4, or 5 substituents, wherein eachsubstituent has one or more carbon, fluorine, chlorine, bromine, oxygen,sulfur, or atoms; and wherein all substituents taken together consist of0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7,8 or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms, 0, 1, 2 or 3 bromineatoms, 0, 1, 2 or 3 oxygen atoms; 0, 1, 2, or 3 sulfur atoms; 0, 1, 2,or 3 nitrogen atoms.

In another embodiment, B has 1, 2, 3, 4, or 5 substituents, wherein eachsubstituent has one or more carbon, fluorine, chlorine, bromine, oroxygen atoms; and wherein all substituents taken together consist of 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7, 8or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms, 0, 1, 2 or 3 bromineatoms, and 0, 1, 2 or 3 oxygen atoms.

In another embodiment, B has a substituent of the formulaC_(a)H_(b)O_(c); wherein a is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, b is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; and cis 0, 1, 2, or 3.

In another embodiment, B has 1, 2, 3, or 4 alkyl substituents having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

In another embodiment, B has a hydroxyalkyl substituent having 0, 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or 2 hydroxy moieties.

In another embodiment, B has an alkyl substituent having 0, 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 carbon atoms.

In another embodiment, B has 1, 2, 3, or 4 halogen substituents.

In another embodiment, B has 1, 2, 3, or 4 chloro substituents.

In another embodiment, B has 1 chloro substituent.

In another embodiment, B has 2 chloro substituents.

In another embodiment, B has 1, 2, 3, or 4 trifluoromethyl substituents.

In another embodiment, B has 1, 2, or 3 trifluoromethyl substituents.

In another embodiment, B has 1 trifluoromethyl substituent.

In another embodiment, B has 2 trifluoromethyl substituents.

In another embodiment, B has a hydroxyl substituent.

Examples of useful moieties for B are depicted below. Each isindividually contemplated as an embodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

In one embodiment, said compound is not

wherein U² is OH or H.

In another embodiment, said compound is not

wherein J³ is O or OH and U² is OH or H.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;

Y is an organic acid functional group, or an amide or ester thereofcomprising up to 14 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced by S or O;or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced by S or O;

U¹ is independently hydrogen; OH; O; S; F; Cl; Br; I; CN; or O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms;

J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃;

Z is S, SO, SO₂, NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl,and B is aryl or heteroaryl;

wherein said compound is not

wherein U² is OH or H.

Compound Example 2

A compound which is a carboxylic acid or a bioisostere thereof, saidcarboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond;

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O; U¹ isindependently hydrogen; OH; O; S; F; Cl; Br; I; CN; or O-alkyl having 1,2, 3, 4, 5 or 6 carbon atoms; J¹ and J² are independently hydrogen; F;Cl, Br; I; O; OH; CN; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms; or CF₃; Z is S, SO, SO₂,NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl, and B is aryl orheteroaryl. Compound Example 3

The compound according to compound example 1 wherein Y is selected fromCO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH,P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

Compound Example 4

The compound according to compound example 1 or 3 of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Compound Example 5

The compound according to compound example 1 or 3 having the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Compound Example 6

The compound according to compound example 1 or 3 having the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Compound Example 7

The compound according to any one of compound examples 1 to 6 wherein Ais (3-methylphenoxy)methyl.

Compound Example 8

The compound according to any one of compound examples 1 to 6 wherein Ais (4-but-2-ynyloxy)methyl.

Compound Example 9

The compound according to any one of compound examples 1 to 6 wherein Ais 2-(2-ethylthio)thiazol-4-yl.

Compound Example 10

The compound according to any one of compound examples 1 to 6 wherein Ais 2-(3-propyl)thiazol-5-yl.

Compound Example 11

The compound according to any one of compound examples 1 to 6 wherein Ais 3-(methoxymethyl)phenyl.

Compound Example 12

The compound according to any one of compound examples 1 to 6 wherein Ais 3-(3-propyl)phenyl.

Compound Example 13

The compound according to any one of compound examples 1 to 6 wherein Ais 3-methylphenethyl.

Compound Example 14

The compound according to any one of compound examples 1 to 6 wherein Ais 4-(2-ethyl)phenyl.

Compound Example 15

The compound according to any one of compound examples 1 to 6 wherein Ais 4-phenethyl.

Compound Example 16

The compound according to any one of compound examples 1 to 6 wherein Ais 4-methoxybutyl.

Compound Example 17

The compound according to any one of compound examples 1 to 6 wherein Ais 5-(methoxymethyl)furan-2-yl.

Compound Example 18

The compound according to any one of compound examples 1 to 6 wherein Ais 5-(methoxymethyl)thiophen-2-yl.

Compound Example 19

The compound according to any one of compound examples 1 to 6 wherein Ais 5-(3-propyl)furan-2-yl.

Compound Example 20

The compound according to any one of compound examples 1 to 6 wherein Ais 5-(3-propyl)thiophen-2-yl.

Compound Example 21

The compound according to any one of compound examples 1 to 6 wherein Ais 6-hexyl.

Compound Example 22

The compound according to any one of compound examples 1 to 6 wherein Ais (Z)-6-hex-4-enyl.

Compound Example 23

The compound according to any one of compound examples 1, 3, 4 and 7 to22 having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 24

The compound according to any one of compound examples 1, 3, and 7 to 22having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 25

The compound according to any one of compound examples 1, 3, and 6 to 22having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 26

The compound according to any one of compound examples 1, 3, and 6 to 22having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 27

The compound according to any one of compound examples 1, 3, and 6 to 22having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 28

The compound according to any one of compound examples 1, 3, and 6 to 22having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 29

The compound according to any one of compound examples 1, 3, and 6 to 22having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 30

The compound according to any one of compound examples 1, 3, and 6 to 22having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 31

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is O.

Compound Example 32

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is S.

Compound Example 33

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is F.

Compound Example 34

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is Cl.

Compound Example 35

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is Br.

Compound Example 36

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is I.

Compound Example 37

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is CN.

Compound Example 38

The compound according to any one of compound examples 1 to 3, and 7 to22 wherein U¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 39

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is hydrogen.

Compound Example 40

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is F.

Compound Example 41

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is Cl.

Compound Example 42

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is Br.

Compound Example 43

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is I.

Compound Example 44

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is O.

Compound Example 45

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is OH.

Compound Example 46

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is CN.

Compound Example 47

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms.

Compound Example 48

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is alkyl having 1, 2, 3, 4, 5, or 6 carbonatoms.

Compound Example 49

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 38, wherein J¹ is CF₃.

Compound Example 50

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is hydrogen.

Compound Example 51

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is F.

Compound Example 52

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is Cl.

Compound Example 53

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is Br.

Compound Example 54

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is I.

Compound Example 55

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is O.

Compound Example 56

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is OH.

Compound Example 57

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is CN.

Compound Example 58

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is O-alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms.

Compound Example 59

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is alkyl having 1, 2, 3, 4, 5, or 6 carbonatoms.

Compound Example 60

The compound according to any one of compound examples 1 to 3, 7 to 22,and 31 to 49 wherein J² is CF₃.

Compound Example 61

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted phenyl.

Compound Example 62

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted thienyl.

Compound Example 63

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted naphthyl.

Compound Example 64

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted furyl.

Compound Example 65

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted pyridinyl.

Compound Example 66

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted benzothienyl.

Compound Example 67

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted indanyl.

Compound Example 68

The compound according to any one of compound examples 1 to 60 wherein Bis substituted or unsubstituted tetralonyl.

Compound Example 69

The compound according to any one of compound examples 1 to 60 wherein Bhas 1, 2, 3, 4, or 5 substituents, wherein each substituent has one ormore carbon, fluorine, chlorine, bromine, or oxygen atoms; and whereinall substituents taken together consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 0, 1,2 or 3 chlorine atoms, 0, 1, 2 or 3 bromine atoms, and 0, 1, 2 or 3oxygen atoms.

Compound Example 70

The compound according to any one of compound examples 1 to 60 wherein Bhas a substituent of the formula C_(a)H_(b)O_(c); wherein a is 0, 1, 2,3, 4, 5, 6, 7, 8 or 9, b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18 or 19; and c is 0, 1, 2, or 3.

Compound Example 71

The compound according to any one of compound examples 1 to 60 wherein Bhas 1, 2, 3, or 4 alkyl substituents having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbon atoms.

Compound Example 72

The compound according to any one of compound examples 1 to 60 wherein Bhas a hydroxyalkyl substituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms and 1 or 2 hydroxy moieties.

Compound Example 73

The compound according to any one of compound examples 1 to 60 wherein Bhas an alkyl substituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms.

Compound Example 74

The compound according to any one of compound examples 1 to 60 wherein Bhas 1, 2, 3, or 4 halogen substituents.

Compound Example 75

The compound according to any one of compound examples 1 to 60 wherein Bhas 1, 2, 3, or 4 chloro substituents.

Compound Example 76

The compound according to any one of compound examples 1 to 60 wherein Bhas 1 chloro substituent.

Compound Example 77

The compound according to any one of compound examples 1 to 60 wherein Bhas 2 chloro substituents.

Compound Example 78

The compound according to any one of compound examples 1 to 60 wherein Bhas 1, 2, 3, or 4 trifluoromethyl substituents.

Compound Example 79

The compound according to any one of compound examples 1 to 60 wherein Bhas 1, 2, or 3 trifluoromethyl substituents.

Compound Example 80

The compound according to any one of compound examples 1 to 60 wherein Bhas 1 trifluoromethyl substituent.

Compound Example 81

The compound according to any one of compound examples 1 to 60 wherein Bhas 2 trifluoromethyl substituents.

Compound Example 82

The compound according to any one of compound examples 1 to 60 wherein Bhas a hydroxyl substituent.

Compound Example 83

The compound according to any one of compound examples 1 to 61 wherein Bis unsubstituted phenyl.

Compound Example 84

The compound according to any one of compound examples 1 to 61 wherein Bis 3,5-dichlorophenyl.

Compound Example 85

The compound according to any one of compound examples 1 to 61 wherein Bis 3,5-di(trifluoromethyl)phenyl.

Compound Example 86

The compound according to any one of compound examples 1 to 61 wherein Bis 2-chlorophenyl.

Compound Example 87

The compound according to any one of compound examples 1 to 61 wherein Bis 3-chlorophenyl.

Compound Example 88

The compound according to any one of compound examples 1 to 61 wherein Bis 4-chlorophenyl.

Compound Example 89

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(trifluoromethyl)phenyl.

Compound Example 90

The compound according to any one of compound examples 1 to 61 wherein Bis 3-isopropylphenyl.

Compound Example 91

The compound according to any one of compound examples 1 to 61 wherein Bis 3-tert-butylphenyl.

Compound Example 92

The compound according to any one of compound examples 1 to 61 wherein Bis 3-hydroxyphenyl.

Compound Example 93

The compound according to any one of compound examples 1 to 61 wherein Bis 3-methoxyphenyl.

Compound Example 94

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(benzoyloxy)phenyl.

Compound Example 95

The compound according to any one of compound examples 1 to 61 wherein Bis 2,3-dimethylphenyl.

Compound Example 96

The compound according to any one of compound examples 1 to 61 wherein Bis 3,4-dimethylphenyl.

Compound Example 97

The compound according to any one of compound examples 1 to 61 wherein Bis 2,4-dimethylphenyl.

Compound Example 98

The compound according to any one of compound examples 1 to 61 wherein Bis 2,5-dimethylphenyl.

Compound Example 99

The compound according to any one of compound examples 1 to 61 wherein Bis 3,5-dimethylphenyl.

Compound Example 100

The compound according to any one of compound examples 1 to 61 wherein Bis 2,6-dimethylphenyl.

Compound Example 101

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(hydroxymethyl)phenyl.

Compound Example 102

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(1-hydroxyethyl)phenyl.

Compound Example 103

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(1-hydroxy-2-methylpropyl)phenyl.

Compound Example 104

The compound according to any one of compound examples 1 to 61 wherein Bis 2-(hydroxymethyl)phenyl.

Compound Example 105

The compound according to any one of compound examples 1 to 61 wherein Bis 4-(hydroxymethyl)-3,5-dimethylphenyl.

Compound Example 106

The compound according to any one of compound examples 1 to 61 wherein Bis 4-(methoxymethyl)-3,5-dimethylphenyl.

Compound Example 107

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(1-hydroxybutyl)phenyl.

Compound Example 108

The compound according to any one of compound examples 1 to 61 wherein Bis 4-(1-methoxybutyl)phenyl.

Compound Example 109

The compound according to any one of compound examples 1 to 61 wherein Bis 4-(1-hydroxybutyl)phenyl.

Compound Example 110

The compound according to any one of compound examples 1 to 61 wherein Bis 4-(2-hydroxyethyl)phenyl.

Compound Example 111

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(2-hydroxyethyl)phenyl.

Compound Example 112

The compound according to any one of compound examples 1 to 61 wherein Bis 2-(2-hydroxyethyl)phenyl.

Compound Example 113

The compound according to any one of compound examples 1 to 61 wherein Bis 4-(2-hydroxyethyl)-3,5-dimethylphenyl.

Compound Example 114

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(1-hydroxyhexyl)phenyl.

Compound Example 115

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(acetoxymethyl)-5-chlorophenyl.

Compound Example 116

The compound according to any one of compound examples 1 to 61 wherein Bis 1-oxo-2,3-dihydro-1H-inden-4-yl.

Compound Example 117

The compound according to any one of compound examples 1 to 61 wherein Bis 1-hydroxy-2,3-dihydro-1H-inden-4-yl.

Compound Example 118

The compound according to any one of compound examples 1 to 61 wherein Bis 5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl.

Compound Example 119

The compound according to any one of compound examples 1 to 61 wherein Bis 3-(1-hydroxy-2-phenylethyl)phenyl.

Compound Example 120

The compound according to any one of compound examples 1 to 61 wherein Bis 4-(2-phenylpropan-2-yl)phenyl.

Compound Example 121

The compound according to any one of compound examples 1 to 60 wherein Bis naphthalen-2-yl.

Compound Example 122

The compound according to any one of compound examples 1 to 60 wherein Bis naphthalen-1-yl.

Compound Example 123

The compound according to any one of compound examples 1 to 60 wherein Bis 4-chloronaphthalen-1-yl.

Compound Example 124

The compound according to any one of compound examples 1 to 3, 7 to 22,and 39 to 123 wherein U¹ is hydrogen.

Compound Example 125

The compound according to any one of compound examples 1 to 3, 7 to 22,and 39 to 123 wherein U¹ is OH.

Compound Example 126

The compound according to compound example 1 or 2 wherein said compoundis not

wherein J³ is O or OH and U² is OH or H.

Compound Example 127

The compound according to any one of compound examples 1 to 125 whereinZ is S.

Compound Example 128

The compound according to any one of compound examples 1 to 125 whereinZ is NH.

Compound Example 129

The compound according to any one of compound examples 1 to 125 whereinZ is NCH₃.

Compound Example 130

The compound according to any one of compound examples 1 to 125 whereinZ is SO.

Compound Example 131

The compound according to any one of compound examples 1 to 125 whereinZ is SO₂.

Compound Example 132

The compound according to any one of compound examples 1 to 125 whereinZ is NSO₂CH₃.

Compound Example 133

The compound according to any one of compound examples 1 to 125 whereinZ is NCOCH₃.

Composition Example

A composition comprising a compound according to any one of compoundexamples 1 to 133, wherein said composition is a liquid which isophthalmically acceptable.

Medicament Examples

Use of a compound according to any one of compound examples 1 to 133 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

Use of a compound according to any one of compound examples 1 to 133 inthe manufacture of a medicament for the treatment of baldness in aperson.

A medicament comprising a compound according to any one of compoundexamples 1 to 133, wherein said composition is a liquid which isophthalmically acceptable.

Method Example

A method comprising administering a compound according to any one ofcompound examples 1 to 133 to a mammal for the treatment of glaucoma orocular hypertension.

Kit Example

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 133, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

“Treatment,” “treat,” or any other form of these words as used hereinare intended to mean use in the diagnosis, cure, mitigation, treatment,or prevention of disease in man or other animals.

H1 through H72 are hypothetical examples of useful compounds.

Synthetic Example 1(Z)-7-[(1R,2R,3R,5R)-5-Chloro-2-(3,5-dichloro-phenylsulfanylmethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (5) Step 1. Mesylation of 1 to Give 2

Triethylamine (26 μL, 0.19 mmol) and methanesulfonyl chloride (12 μL,0.15 mmol) were added sequentially to a solution of(Z)-7-[(1R,2S,3R,5R)-5-chloro-2-hydroxymethyl-3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-hept-5-enoicacid allyl ester (1, see U.S. Provisional Patent Application No.60/757,696, filed Jan. 10, 2006, which is incorporated by referenceherein; 50 mg, 0.125 mmol) in CH₂Cl₂ (1.25 mL) at 0° C. The reactionmixture was allowed to warm to room temperature. After 3 d at roomtemperature, the reaction mixture was partitioned between saturatedaqueous NaHCO₃ (5 mL) and CH₂Cl₂ (5 mL). The phases were separated andthe aqueous phase was extracted with CH₂Cl₂ (2×5 mL). The combinedextracts were washed with brine (5 mL), dried (MgSO₄), filtered andconcentrated in vacuo to afford crude mesylate 2 which was used withoutfurther purification.

Step 2. Reaction of 2 to Give Thiol 3

A solution of 3,5-dichlorobenzenethiol (78 mg, 0.44 mmol) in DMF (3 mL)was added to a suspension of sodium hydride (60 wt % in oil, 17 mg, 0.43mmol) in DMF (1 mL) at room temperature. After 30 min at roomtemperature, a solution of mesylate 2 (crude, ˜0.125 mmol) in THF (1.2mL) was added. After 1 h, the reaction mixture was heated at 35° C.After 18 h at 35° C., the reaction mixture was partitioned betweenaqueous HCl (0.1 N, 20 mL) and EtOAc (20 mL). The phases were separatedand the organic phase was washed with H₂O (15 mL) and brine (15 mL),dried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on 40 g of silica gel (100%hexane →100% EtOAc, gradient) afforded 20 mg (29% over two steps) ofthiol 3.

Step 3. Deprotection of 3 to Give 4

Pyridinium p-toluenesulfonate (PPTs, 1 mg, 0.004 mmol) was added to asolution of 3 (20 mg, 0.035 mmol) in methanol (0.35 mL) at roomtemperature under nitrogen. The solution was heated at 40° C. overnight,then cooled and concentrated in vacuo. Purification of the crude residueby flash column chromatography on 4 g of silica gel (100% hexane→100%EtOAc, gradient) afforded 11 mg (65%) of alcohol 4.

Step 4. Saponification of 4 to Give 5

Lithium hydroxide (92 μL of a 1.0 M aqueous solution, 0.092 mmol) wasadded to a solution of ester 4 (11 mg, 0.023 mmol) in THF (0.1 mL).After stirring overnight at room temperature, the reaction mixture waspartitioned between aqueous HCl (0.1 N, 5 mL) and EtOAc (5 mL). Thephases were separated and the aqueous phase was extracted with EtOAc(2×5 mL). The combined extracts were dried (MgSO₄), filtered andconcentrated in vacuo to afford 8 mg (79%) of the title compound (5).

Synthetic Example 2(Z)-7-((1R,2S,3R,5R)-2-{[Acetyl-(3,5-dichloro-phenyl)-amino]-methyl}-5-chloro-3-hydroxy-cyclopentyl)-hept-5-enoicacid (10) Step 1. Oxidation of 1 to Give 6

DMSO (47 μL, 0.66 mmol) was added to a solution of oxalyl chloride (26μL, 0.29 mmol) in CH₂Cl₂ (0.25 mL) at −78° C. After 15 min, a solutionof alcohol 1 (125 mg, 0.31 mmol) in CH₂Cl₂ (0.5 mL+0.5 mL rinse) wasadded. After 15 min at −78° C., triethylamine (272 μL, 1.95 mmol) wasadded and the reaction was allowed to warm to room temperature. After 1h at room temperature the reaction mixture was partitioned betweensaturated aqueous NaHCO₃ (3 mL) and CH₂Cl₂ (5 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (2×5 mL). Thecombined extracts were dried (MgSO₄), filtered and concentrated invacuo. Purification of the crude residue by flash column chromatographyon silica gel (30% EtOAc/hexane) afforded 90 mg (72%) of aldehyde 6.

Step 2. Reduction Amination to Give 7

3,5-Dichloroaniline (57 mg, 0.35 mmol) was added to a solution ofaldehyde 6 (90 mg, 0.23 mmol) in CH₂Cl₂ (1.75 mL) at room temperature.After 1 h, sodium triacetoxyborohydride (74 mg, 0.35 mmol) was added.After 18 h at room temperature, the reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (5 mL) and CH₂Cl₂ (5 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (2×5 mL).The combined extracts were washed with brine (5 mL), dried (MgSO₄),filtered and concentrated in vacuo. Purification of the crude residue byflash column chromatography on 4 g of silica gel (100% hexane→100%EtOAc, gradient) afforded 120 mg of an inseparable mixture of desiredproduct 7 and 3,5-dichloroaniline which was used without furtherpurification.

Step 3. Acylation of 7 to Give 8

Pyridine (17 μL, 0.21 mmol) and acetyl chloride (14 μL, 0.20 mmol) wereadded sequentially to a solution of impure amine 7 (˜32 mg, ˜0.059 mmol)in CH₂Cl₂ (0.1 mL) at 0° C. The reaction mixture was allowed to warm toroom temperature. After 18 h at room temperature the reaction mixturewas partitioned between saturated aqueous NaHCO₃ (2 mL) and CH₂Cl₂ (5mL). The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (5 mL). The combined extracts were washed with brine (2 mL),dried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on 4 g of silica gel (100%hexane →100% EtOAc, gradient) afforded 22 mg (64%) of acetate 8.

Step 4. Deprotection of 8 to Give 9

PPTs (1 mg, 0.004 mmol) was added to a solution of 8 (22 mg, 0.037 mmol)in methanol (0.38 mL) at room temperature under nitrogen. The solutionwas heated at 40° C. overnight, then cooled and concentrated in vacuo.Purification of the crude residue by flash column chromatography on 4 gof silica gel (100% hexane →100% EtOAc, gradient) afforded 19 mg(quant.) of alcohol 9.

Step 5. Deprotection of 9 to Give 10

Pyrrolidine (3 μL, 0.036 mmol) andtetrakis(triphenylphosphine)palladium(0) (2 mg, 0.0017 mmol) were addedto a solution of allyl ester 9 (19 mg, 0.038 mmol) in CH₂Cl₂ (0.4 mL).After stirring overnight at room temperature, the reaction mixture waspartitioned between aqueous HCl (1 N, 5 mL) and CH₂Cl₂ (5 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(2×5 mL). The combined extracts were dried (MgSO₄), filtered andconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on 4 g of silica gel (2×, 10% MeOH/CH₂Cl₂) afforded 5 mg(29%) of the title compound (10).

Synthetic Example 3(Z)-7-{(1R,2S,3R,5R)-5-Chloro-2-[(3,5-dichloro-phenylamino)-methyl]-3-hydroxy-cyclopentyl}-hept-5-enoicacid (11)

Lithium hydroxide (21 μL of a 1.0 M aqueous solution, 0.021 mmol) wasadded to a solution of acetate 10 (2 mg, 0.004 mmol) in THF (0.2 mL).After stirring 3 d at room temperature, the reaction mixture waspartitioned between aqueous HCl (1.0 N, 2 mL) and EtOAc (2 mL). Thephases were separated and the aqueous phase was extracted with EtOAc (2mL). The combined extracts were dried (MgSO₄), filtered and concentratedin vacuo to afford 1 mg (55%) of the title compound (11).

Synthetic Example 45-(3-((1R,2S,3R,5R)-5-chloro-2-((3,5-dichlorophenylamino)methyl)-3-hydroxycyclopentyl)propyl)-thiophene-2-carboxylicacid (15) Step 1. Reduction Amination to Give 13

Sodium triacetoxyborohydride (132 mg, 0.62 mmol) was added in oneportion to a solution of 3,5-dichloroaniline (101 mg, 0.63 mmol) wasadded to a solution of aldehyde 12 (see U.S. Provisional PatentApplication No. 60/947,904, filed Jul. 3, 2007, which is incorporated byreference herein, 130 mg, 0.31 mmol) in CH₂Cl₂(3.1 mL) at roomtemperature. After 3 d at room temperature, the reaction mixture waspartitioned between saturated aqueous NaHCO₃ (5 mL) and CH₂Cl₂(10 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂(2×10 mL). The combined organic phase was dried (MgSO₄), filteredand concentrated in vacuo. Purification of the crude residue bychromatography on 12 g of silica gel (100% hexane →100% EtOAc, gradient)afforded 100 mg (57%) of desired product 13.

Step 4. Deprotection of 13 to Give 14

PPTs (1 mg, 0.004 mmol) was added to a solution of 13 (30 mg, 0.053mmol) in methanol (0.5 mL) at room temperature under nitrogen. Thesolution was heated at 40° C. for 18 h, then cooled and concentrated invacuo. Purification of the crude residue by chromatography on 4 g ofsilica gel (100% hexane→100% EtOAc, gradient) afforded 20 mg (78%) ofalcohol 14.

Step 5. Saponificaton of 14 to Give 15

Lithium hydroxide (0.20 mL of a 1.0 M aqueous solution, 0.20 mmol) wasadded to a solution of ester 14 (20 mg, 0.042 mmol) in THF (0.2 mL).After stirring at 40° C. for 18 h, the reaction mixture was cooled andpartitioned between aqueous HCl (0.1 N, 5 mL) and EtOAc (5 mL). Thephases were separated and the aqueous phase was extracted with EtOAc(2×5 mL). The combined extracts were washed with brine (5 mL), dried(MgSO₄), filtered and concentrated in vacuo. Purification of the cruderesidue by chromatography on 4 g of silica gel (100% hexane→100% EtOAc,gradient) afforded 4 mg (21%) of the title compound (15).

Synthetic Example 55-(3-((1R,2R,3R,5R)-5-chloro-2-((3,5-dichlorophenylthio)methyl)-3-hydroxycyclopentyl)propyl)-thiophene-2-carboxylicacid (20) Step 1. Mesylation of 16 to Give 17

Triethylamine (25 μL, 0.18 mmol) and methanesulfonyl chloride (11 μL,0.14 mmol) were added sequentially to a solution of alcohol 16 (see U.S.patent application Ser. No. 11/764,929 filed Jun. 19, 2007, which isincorporated by reference herein, 50 mg, 0.12 mmol) in CH₂Cl₂ (1.2 mL)at 0° C. The reaction mixture was allowed to warm to room temperature.After 3 h at room temperature, the reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (5 mL) and CH₂Cl₂ (5 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (2×5 mL).The combined extracts were washed with water (5 mL) and brine (5 mL),dried (MgSO₄), filtered and concentrated in vacuo to afford crudemesylate 17 which was used without further purification.

Step 2. Reaction of 17 to Give Thiol 18

Sodium hydride (60 wt % in oil, 17 mg, 0.42 mmol) was added to asolution of 3,5-dichlorobenzenethiol (75 mg, 0.42 mmol) in DMF (4 mL) inDMF (1 mL) at room temperature. After 30 min at room temperature, asolution of mesylate 17 (crude, ˜0.12 mmol) in THF (1.2 mL) was addedvia syringe and the reaction mixture was heated at 60° C. After 18 h at60° C., the reaction mixture was cooled and partitioned between water(10 mL) and EtOAc (20 mL). The phases were separated and the aqueousphase was extracted with EtOAc (2×10 mL). The combined organic phase waswashed brine (15 mL), dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude residue by chromatography on 12 g of silicagel (100% hexane→100% EtOAc, gradient) afforded 10 mg (14% over twosteps) of thiol 18.

Step 3. Deprotection of 18 to Give 19

PPTs (4.3 mg, 0.017 mmol) was added to a solution of 18 (10 mg, 0.017mmol) in methanol (0.17 mL) at room temperature under nitrogen. Thesolution was heated at 40° C. overnight, then cooled and concentrated invacuo. Purification of the crude residue by chromatography on 4 g ofsilica gel (100% hexane→100% EtOAc, gradient) afforded 8 mg (94%) ofalcohol 19.

Step 4. Saponification of 19 to Give 20

In accordance with the procedures of example 4, step 5, ester 19 (8 mg,0.016 mmol) was converted into 6 mg (77%) of the title compound (20).

Synthetic Example 65-(3-((1R,2R,3R,5R)-5-chloro-2-((3,5-dichlorophenylsulfinyl)methyl)-3-hydroxycyclopentyl)propyl)-thiophene-2-carboxylicacid (22) Step 1. Oxidation of 19 to Give 21

A solution of sodium periodate (9 mg, 0.042 mmol) in water (0.2 mL) wasadded to a solution of thiol 19 (10 mg, 0.020 mmol) in MeOH (0.2 mL).After stirring at room temperature overnight, the reaction mixture wasdried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by preparative thin layer chromatography on 4 g of silicagel (10% MeOH/CH₂Cl₂) afforded 3 mg (29%) of sulfoxide 21.

Step 2. Saponification of 21 to Give 22

Lithium hydroxide (0.05 mL of a 1.0 M aqueous solution, 0.05 mmol) wasadded to a solution of ester 21 (3 mg, 0.0059 mmol) in THF (0.05 mL) ina one dram vial and the vial was fitted with a screw top cap. Afterstirring room temperature for 5 d, the reaction mixture acidified withaqueous HCl (1.0 N, 1 mL) and extracted with CH₂Cl₂ (5 mL). The organicphase was dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude residue by preparative thin layerchromatography on 4 g of silica gel (10% MeOH/CH₂Cl₂) afforded 1 mg(34%) of the title compound (22).

Synthetic Example 75-(3-((1R,2R,3R,5R)-5-chloro-2-((3,5-difluorophenylthio)methyl)-3-hydroxycyclopentyl)propyl)-thiophene-2-carboxylicacid (25) Step 1. Reaction of 17 to Give Thiol 23

Sodium hydride (60 wt % in oil, 115 mg, 2.88 mmol) was added to asolution of 3,5-difluorbenzenethiol (421 mg, 2.88 mmol) in DMF (20 mL)at room temperature. After 30 min at room temperature, a solution ofmesylate 17 (crude, prepared from 16 (300 mg, 0.72 mmol) in accordancewith the procedures of example 5, step 1, ˜0.72 mmol) in THF (7.2 mL)was added via syringe and the reaction mixture was heated at 40° C.After 3 d at 40° C., the reaction mixture was cooled and partitionedbetween aqueous HCl (1.0 N, 10 mL) and EtOAc (50 mL). The phases wereseparated and the aqueous phase was extracted with EtOAc (2×10 mL). Thecombined organic phase was washed water (50 mL) and brine (50 mL), dried(MgSO₄), filtered and concentrated in vacuo to afford crude thiol 23which was used without further purification.

Step 2. Deprotection of 23 to Give 24

PPTs (18 mg, 0.072 mmol) was added to a solution of thiol 23 (crude,˜0.72 mmol) in methanol (24 mL) at room temperature under nitrogen. Thesolution was heated at 40° C. overnight, then cooled and concentrated invacuo. Purification of the crude residue by chromatography on 12 g ofsilica gel (100% hexane →100% EtOAc, gradient) afforded 7 mg (2%) ofpure alcohol 24 and 125 mg of 24 contaminated with an impurity.

Step 3. Saponification of 24 to Give 25

Ester 24 (7 mg, 0.015 mmol) was converted into 4 mg (59%) of the titlecompound (25) in accordance with the procedures of example 4, step 5,with the following modifications: the extraction was carried out withCH₂Cl₂ instead of EtOAc and the chromatography gradient was CH₂Cl₂→10%MeOH/CH₂Cl₂.

The α-chain A may be modified may be varied by following or adaptingprocedures found in U.S. patent application Ser. No. 11/764,929, filedJun. 19, 2007, which is expressly incorporated by reference herein,wherein an analog of the Corey lactone is used as the precursor to aWittig reaction to install all the atoms of the α-chain; other Wittigreactions and the preparation of the requisite phosphonates aredescribed by Collect. Czech. Chem. Commun. 1994, 58, 138-148, andCollect. Czech. Chem. Commun. 1994, 59, 2533-2544. Alternatively, theintermediate Corey lactone analog may be reduced to the correspondingprimary alcohol, which may then be manipulated by methods known in theart to compounds bearing a heteroatom at the 5th (by alkylation of thealcohol or the derived thiol), 4th (by lengthening the chain by one atom(e.g. by homologation via the corresponding aldehyde)) or 6th (byshortening the chain by one atom (e.g. by ozonolysis of an enol etherderived from the corresponding aldehyde)) atom from the acid terminus.

Different J¹, J², and U¹ substituents may be obtained by following oradapting procedures found in the following documents, all of which areexpressly incorporated by reference herein:

U.S. patent application Ser. No. 11/764,929;U.S. patent application Ser. No. 11/738,307, filed on Apr. 20, 2007;U.S. patent application Ser. No. 11/690,678, filed on May 23, 2007;U.S. patent application Ser. No. 11/742,987 filed on May 1, 2007; andU.S. patent application Ser. No. 11/747,478, filed on May 11, 2007.

Analogs of 3,5-dichloroaniline may be obtained commercially, or preparedfrom commercially available nitroaryl compounds by reduction. Otheraromatic (or heteroaromatic) amines may be prepared from thecorresponding aryl (or heteroaryl) halide or sulfonate by usingbenzophenone imine and following or adapting procedures described byBuchwald, et al. (e.g. J. Org. Chem. 2006, 71, 430-433 and TetrahedronLett. 1997, 38, 6367-6370). Alternatively, the intermediatehydroxymethyl moiety (in compounds such as 1 and its analogs) may beconverted to the corresponding primary amine, for example, via asulfonate intermediate reacting with sodium azide, followed by reductionto a primary amine. This amine may then be arylated (or heteroarylated)via the Buchwald procedure described above.

Analogs of 3,5-dichlorobenzenethiol may be obtained commercially. Otheraromatic (or heteroaromatic) sulfides may be prepared from thecorresponding aryl (or heteroaryl) halide or sulfonate and a silyl-SH oralkyl-SH analog (followed by desilylation or dealkylation to reveal therequisite thiol) by following or adapting procedures described byBuchwald (e.g. Tetrahedron 2004, 60, 7397-7403) and Hartwig (e.g. J. Am.Chem. Soc. 2006, 128, 2180-2181). Alternatively, the nucleophilicaromatic substitution of NaSH with an appropriate aryl or heteroarylhalide may be accomplished by adapting methods known in the art (e.g.see Peach, in Patai, “The Chemistry of the Thiol Group,” pt. 2, pp735-744, Wiley, New York, 1974). In another alternative approach, theintermediate hydroxymethyl moiety (in compounds such as 1 and itsanalogs) may be converted to the corresponding thiol (e.g. via asulfonate intermediate reacting with sodium thioacetate, followed bydeacylation). This thiol then may be arylated (or heteroarylated) onsulfur using an appropriate aryl (or heteroaryl) halide or sulfonate(see Buchwald and Hartwig references above).

Oxidation of the sulfur atom to either to the sulfoxide or the sulfoneanalog may be readily accomplished by methods known in the art.

The compounds disclosed herein are believed to be selectiveprostaglandin EP₂ agonists, and are thus useful for the treatment ofglaucoma, ocular hypertension, and other diseases or conditions.

In Vitro Testing

U.S. patent application Ser. No. 11/553,143, filed on Oct. 26, 2006,incorporated by reference herein, describes the methods used to obtainthe in vitro data in the table below.

EP2 data EP4 data flipr cAMP flipr Other Receptors (EC50 in nM)Structure EC50 EC50 Ki EC50 KI hFP hEP1 hEP3A hTP hIP hDP

3364 0.4 22 >10000 376 NA NA >10000 1718 >10000 >10000

6371 29 2090 NT >10000 NA NA 2683 >10000 NA

135 0.5 18 >10000 1034 NA NA >10000 >10000 >10000 NA

>10000 110 336 NT NA NA NA NA NA NA NA

59 0.11 0.3 >10000 828 NA NA NA NA NA NA

101 0.4 12 >10000 NA NA NA 4209 NA NA

850 1.3 9 >10000 2332 NA NA NA NA

IN VIVO EXAMPLES

U.S. Pat. No. 7,091,231 describes the methods used for these in vivotests.

In Vivo Example 1

5-(3-((1R,2R,3R,5R)-5-chloro-2-((3,5-dichlorophenylthio)methyl)-3-hydroxycyclopentyl)propyl)-thiophene-2-carboxylicacid (20) was tested in normotensive dogs at 0.01%, dosing once dailyfor 5 days. The maximum intraocular pressure (IOP) decrease frombaseline was 6.3 mmHg (35%) at 6 h; the maximum ocular surface hyperemia(OSH) score was 1.7 at 52 h.

In Vivo Example 2

The composition and dosage regimen of In vivo example 1 was also testedin laser-induced hypertensive monkeys, using one single day dose. At0.01%, the maximum IOP decrease from baseline was 13.9 mmHg (40%) at 24h.

In Vivo Example 3

The composition and dosage regimen of In vivo example 1 may also be usedto reduce IOP in humans.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention. However, it isapparent for one of ordinary skill in the art that further compoundswith the desired pharmacological properties can be prepared in ananalogous manner, and that the disclosed compounds can also be obtainedfrom different starting compounds via different chemical reactions.Similarly, different pharmaceutical compositions may be prepared andused with substantially the same result. Thus, however detailed theforegoing may appear in text, it should not be construed as limiting theoverall scope hereof; rather, the ambit of the present invention is tobe governed only by the lawful construction of the claims.

1. A compound having a formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond; Y isan organic acid functional group, or an amide or ester thereofcomprising up to 14 carbon atoms; or Y is hydroxymethyl or an etherthereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced by S or O;or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced by S or O; U¹ is independently hydrogen; OH; O; S;F; Cl; Br; I; CN; or O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; J¹and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃; Z is S, SO, SO₂, NR, NCOR, or NSO₂R, wherein R isH or C₁₋₆ hydrocarbyl, and B is aryl or heteroaryl.
 2. A compound whichis a carboxylic acid or a bioisostere thereof, said carboxylic acidhaving a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein a dashed line represents the presence or absence of a bond; A is—(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O; U¹ isindependently hydrogen; OH; O; S; F; Cl; Br; I; CN; or O-alkyl having 1,2, 3, 4, 5 or 6 carbon atoms; J¹ and J² are independently hydrogen; F;Cl, Br; I; O; OH; CN; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms; or CF₃; Z is S, SO, SO₂,NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl, and B is aryl orheteroaryl.
 3. The compound of claim 1 wherein Y is selected from CO₂R²,CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂,CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.
 4. The compound of claim of claim 3 wherein B issubstituted or unsubstituted phenyl or substituted or unsubstitutedpyridinyl.
 5. The compound of claim of claim 4 wherein B is substitutedor phenyl.
 6. The compound of claim 4 having the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 7.The compound of claim 6 wherein B is phenyl having from 0 to 4substituents independently selected from F, Cl, Br, C₁₋₃ alkyl, and C₁₋₃alkoxy.
 8. The compound of claim 4 wherein A is5-(3-propyl)thiophen-2-yl.
 9. The compound of claim 4 wherein A is(Z)-6-hex-4-enyl.
 10. The compound of claim 4 wherein U¹ is OH.
 11. Thecompound of claim 4 wherein J¹ is hydrogen.
 12. The compound of claim 4wherein J² is Cl.
 13. The compound of claim 7 wherein Z is S.
 14. Thecompound of claim 7 wherein Z is SO.
 15. The compound of claim 7 whereinZ is NH.
 16. The compound of claim 7 wherein Z is NCOCH₃.
 17. Thecompound of claim 6 wherein J¹ is hydrogen; U¹ and J² are independentlyselected from F, Cl, and OH; and Z is S, SO, NH, or NCOR.
 18. A methodof reducing intraocular pressure comprising administering a compound ofclaim 1 to a mammal in need thereof.
 19. A method of treating glaucomacomprising administering a compound of claim 1 to a mammal in needthereof.
 20. Use of a compound according to claim 1 in the manufactureof a medicament for the reduction of intraocular pressure or thetreatment of glaucoma in a mammal.